Cell proliferation and cell death in the developing chick inner ear: Spatial and temporal patterns

Lang, Hainan; Bever, Michele Miller; Fekete, Donna M.

doi:10.1002/(sici)1096-9861(20000207)417:2<205::aid-cne6>3.0.co;2-y

Cited by 70 publications

(66 citation statements)

References 60 publications

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“…Apoptosis was detected using an antibody to activated Caspase 3, while cell proliferation was detected using an antibody to the M-phase marker phospho-Histone H3. At this stage, Brn4− embryos (n=4) exhibited regional apoptosis in the lateral wall of the basal cochlea, similar to what has been reported in WT embryos (Lang et al 2000;Nishikori et al 1999) (Fig. 5A).…”

Section: Abnormal Spiral Ligament Fibrocytes In Mutant Micesupporting

confidence: 85%

Cooperative Function of Tbx1 and Brn4 in the Periotic Mesenchyme is Necessary for Cochlea Formation

Braunstein

Crenshaw

Morrow

et al. 2008

JARO

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The T-box transcription factor TBX1 has been identified as the major gene responsible for the etiology of velocardiofacial syndrome/DiGeorge syndrome (VCFS/DGS). Conductive hearing loss occurs in a majority of patients with this syndrome, while sensorineural deafness has also been reported in some cases. Mutations in POU3F4/BRN4, a POU domain transcription factor, cause DFN3, an X-linked nonsyndromic form of deafness characterized by mixed conductive and sensorineural hearing loss. Inactivation of the murine orthologues of these genes causes similar defects to those seen in humans and has provided excellent models for the study of inner ear development. Tbx1 and Brn4 are expressed in the mesenchymal cells surrounding the otic vesicle and have been shown to play roles in cochlear outgrowth. Furthermore, expression of Brn4 is reduced in Tbx1 null mutants, suggesting a possible genetic interaction between these genes. To test whether Tbx1 and Brn4 function in a common pathway, mice mutant for both genes were generated and analyzed for inner ear defects. Brn4−;Tbx1+/− mutants displayed a significant reduction in the number of turns of the cochlea compared to Brn4− or Tbx1+/− mice. In addition, Brn4−;Tbx1+/− mice displayed structural defects in the apical cochlea indicative of Mondini dysplasia found in patients with either VCFS/DGS or DFN3. These data establish a genetic interaction between Tbx1 and Brn4 relevant to human disease and indicate a function of these genes in signaling from the periotic mesenchyme to the otic vesicle to direct proper coiling of the cochlear duct.

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Section: Abnormal Spiral Ligament Fibrocytes In Mutant Micesupporting

confidence: 85%

Cooperative Function of Tbx1 and Brn4 in the Periotic Mesenchyme is Necessary for Cochlea Formation

Braunstein

Crenshaw

Morrow

et al. 2008

JARO

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“…These extra cells seem to be mainly localized to the ventral otic epithelium at these time points. This is where six1 is normally expressed and is a hot spot for cell division (Lang et al, 2000) and cell death (Bever and Fekete, 1999) during inner ear development. However, some of the extra dividing and dying cells are observed in more dorsal positions and suggest that six1 could have a non-cell autonomous function, although we cannot rule out the possibility of cell mixing, as has been shown in the developing Xenopus inner ear (Kil and Collazo, 2001).…”

Section: Six1 Affects Hair Cell and Neuronal Number Through Differentmentioning

confidence: 99%

The Transcription Factorsix1Inhibits Neuronal and Promotes Hair Cell Fate in the Developing Zebrafish (Danio rerio) Inner Ear

Bricaud¹,

Collazo²

2006

J. Neurosci.

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The developmental processes leading to the differentiation of mechanosensory hair cells and statoacoustic ganglion neurons from the early otic epithelium remain unclear. Possible candidates include members of the Pax-Six-Eya-Dach ( paired box-sine oculis homeobox-eyes absent-dachshund) gene regulatory network. We cloned zebrafish six1 and studied its function in inner ear development. Gain-and loss-of-function experiments show that six1 has opposing roles in hair cell and neuronal lineages. It promotes hair cell fate and, conversely, inhibits neuronal fate by differentially affecting cell proliferation and cell death in these lineages. By independently targeting hair cells with atoh1a (atonal homolog 1a) knockdown or neurons with neurog1 (neurogenin 1) knockdown, we showed that the remaining cell population, neurons or hair cells, respectively, is still affected by gain or loss of six1 function. six1 interacts with other members of the Pax-Six-Eya-Dach regulatory network, in particular dacha and dachb in the hair cell but not neuronal lineage. Unlike in mouse, six1 does not appear to be dependent on eya1, although it seems to be important for the regulation of eya1 and pax2b expression in the ventral otic epithelium. Furthermore, six1 expression appears to be regulated by pax2b and also by foxi1 ( forkhead box I1) as expected for an early inducer of the otic placode. Our results are the first to demonstrate a dual role for a member of the Pax-Six-Eya-Dach regulatory network in inner ear development.

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“…Morphological hallmarks of apoptosis, such as shrunken cytoplasm and condensed pyknotic nuclei, are readily observable in hematoxylin-and eosin-stained or hematoxylin-counterstained sections (Kerr et al 1995;Lang et al 2000). The left panel of Figure 3 illustrates the progressive apoptosis in SGNs induced by ouabain exposure.…”

Section: Translocation Of Cytochrome C and Apoptosismentioning

confidence: 99%

Ouabain Induces Apoptotic Cell Death in Type I Spiral Ganglion Neurons, but not Type II Neurons

Lang

Schulte

Schmiedt

2005

JARO

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Application of ouabain to the intact round-window (RW) membrane of the gerbil cochlea induces apoptosis in most spiral ganglion neurons (SGNs), leaving a few neurons intact (Schmiedt et al. 2002). Here, physiological measures and immunostaining were used to examine the process of SGN degeneration at 3, 6, 12, and 24 h, 4 days, and 1 and 5 months after ouabain treatment. The few remaining neurons surviving up to 5 months after ouabain treatment were immunoreactive for peripherin, a type II neuron marker. Peripherin-positive cell counts indicate that about 7% of the SGNs in the gerbil cochlea are type II neurons, and these neurons survive intact after ouabain treatment. Ouabain exposure had little effect on the outer hair cell and lateral wall systems, even after a 5 month loss of auditory-nerve function. The cellular locations of cytochrome c, poly (ADP-ribose) polymerase (PARP), and activated caspase 3 were examined in control and ouabain-treated cochleas. A redistribution of cytochrome c in peripherinnegative (type I) neurons was observed at 3 h after ouabain exposure. Degraded PARP and activated caspase 3 were also detected in peripherin-negative SGNs at 6 and 24 h after treatment, respectively. These results suggest that the redistribution of cytochrome c is an early event during apoptosis in type I SGNs and that activation of PARP and caspase 3 are associated with apoptosis in these cells. Calcineurin and NF-kB are two important signaling pathways that may modulate cell survival in the central nervous system. Here, we found that calcineurin and NF-kB selectively labeled type II neurons. It is speculated that the high levels of calcineurin and NF-kB in type II SGNs, as compared with type I SGNs, may play protective roles in enhancing the survival of type II neurons exposed to ouabain.

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Cell proliferation and cell death in the developing chick inner ear: Spatial and temporal patterns

Cited by 70 publications

References 60 publications

Cooperative Function of Tbx1 and Brn4 in the Periotic Mesenchyme is Necessary for Cochlea Formation

Cooperative Function of Tbx1 and Brn4 in the Periotic Mesenchyme is Necessary for Cochlea Formation

The Transcription Factorsix1Inhibits Neuronal and Promotes Hair Cell Fate in the Developing Zebrafish (Danio rerio) Inner Ear

Ouabain Induces Apoptotic Cell Death in Type I Spiral Ganglion Neurons, but not Type II Neurons

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